dementia has reached epidemic proportions in our aging society, and most affected are thought to have Alzheimer's Disease (AD). Clinical diagnostic accuracy is only about 80% and neuropathological diagnosis presents some difficulty. The cause of D is unknown. It is suspected that AD is heterogeneous. There are also overlaps of AD with Parkinson's disease and vascular dementia. The objectives of this proposal are to apply objective clinical measures to more accurately diagnose AD and to follow these patients and controls in a longitudinal study. Clinical data will be correlated with neuropathological analysis. A patient data base (patient registry) and tissue repository (brain bank) will support these studies. Three major clinical research projects concern heterogeneity: one will assess the extrapyramidal subtype using clinical, electrophysiological and biochemical measures; a related pilot project assesses postural control and vestibular function measures as diagnostic tools for this subtype and another pilot explores new probes for dopamine-2 receptors as another biochemical tool. Another major clinical project investigates genetic heterogeneity by HLA markers. The third clinical project applies hemorheological methods to study the role of the cerebral circulation in AD and vascular dementia. These research efforts are aimed at better understanding different patient populations with subtypes of AD and the different factors which may contribute to the cause. Both clinical and biochemical markers may therefore not only provide a better means of diagnosis but may eventually result in understanding etiology and therapy. Another pilot is aimed at developing better immunochemical probes for beta-amyloid which may be useful in diagnosis and for assessing the potential existence of abnormal forms of the protein in AD as a possible basic mechanism in causality. Another pilot, purely basic in design, examines the role of glutamine in memory mechanisms in the rat hippocampus by studying the influence of cholinergic inputs on excitatory synaptic transmission in dissociated cultures of hippocampus with voltage and patch clamp techniques. In addition to the above, a beginning is made to study possible ameliorative therapies in a pilot project which evaluates bright light or melatonin administration as possible treatment for disturbance in sleep/wake cycles in AD. There is also a therapeutic feasibility trial using synvinolin (an analog of lovastatin which lowers cholesterol) in AD and vascular dementia who have rheological abnormalities.